The interaction of calmodulin with several of its target proteins including cyclic nucleotide phosphodiesterase, adenylate cyclase, myosin light chain kinase, phosphorylase kinase, cAMP dependent protein kinase, calcineurin and troponin I has been studied in order to understand the mechanism of regulation of Ca++-dependent cellular processes by this protein. At physiological concentrations of KCl binding of Ca++ to its specific sites on calmodulin generates stepwise conformational transitions. The different Ca++-dependent interactions of calmodulin with its several protein targets allow calmodulin to effect a specific kinetic regulation of the Ca++ signal. In contrast to phosphorylase kinase which interacts with calmodulin in the absence of Ca++, cAMP phosphodiesterase needs Ca++ for interaction. This enzyme exhibits a highly cooperative Ca++ activation and different degrees of Ca++ occupancy are needed for interaction and activation. Enzyme activity can be modulated by factors which alter either calmodulin or Ca++ levels. A third regulatory mechanism involves the interaction of the two second messengers, Ca++ and cAMP. These are closely linked at the levels of phosphorylation of the target proteins, regulation of cyclic nucleotide and Ca++ concentrations and also by virtue of interactions between the regulatory subunit of protein kinase and calmodulin.